Nuclear receptors (NRs) are transcription factors whose activity is regulated by the binding of small lipophilic ligands, including hormones, vitamins, and metabolites. Pharmacological NR ligands serve as important therapeutic agents; for example, all-trans retinoic acid, an activating ligand for retinoic acid receptor α (RARα), is used to treat leukemia. Another RARα ligand, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4- dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid (Ro 41-5253), is a potent antagonist that has been a useful and purportedly specific probe of RARα function. Here, we report that Ro 41-5253 also activates the peroxisome proliferatoractivated receptor γ (PPARγ), a master regulator of adipocyte differentiation and target of widely prescribed antidiabetic thiazolidinediones (TZDs). Ro 41-5253 enhanced differentiation of mouse and human preadipocytes and activated PPARγ target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARγ protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARγ-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARα agonist or by depleting cells of RARα, indicating that PPARγ activation was not related to RARα antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARγ, suggesting that Ro 41-5253 directly affects PPAR activity. These results vividly demonstrate that pharmacological NR ligands may have "off-target" effects on other NRs. Ro 41-5253 is a PPARγ agonist as well as an RARα antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.
ASJC Scopus subject areas
- Molecular Medicine